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Buket Aksu

on 20 November 2014

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Phd. Pharm. Buket AKSU
BC 2000: Take and eat this root
AC 1000: That root is bad, come and read this prayer
AC 1850: That prayer is superstition, take and drink this elixir
AC 1940: That elixir is snake oil, take and swallow this pill
AC 1985: That pill is ineffective, come and take this antibiotic
AC 2000: That antibiotic no longer works, "come and eat this root"

Improves the decision making process
Ensures to identify how the best benefit is assured for the patient
Based on science and acts with concrete data
Ensures minimization of subjective approaches
Classifies and Prioritize risks
Ensures better utilization of resources

History of Medicines
Comes from a Latin origin term called "Qualitas", it was adopted in French as "qualité" and adopted in Turkish with its French pronunciation as "kalite".
"The nature, attribute of something or someone"
"A thing's characteristics of being good or bad"
"Superiority and perfection in any term"

FDA announced the advancements in the current Good Manufacturing Practices (cGMP) to the pharmaceutical industry in 2002

Development Process of Quality in the Drug Industry
Lean Manufacturing
Six Sigma
Lean Six Sigma
FDA cGMP Initiative
FDA PAT Guidelines
Lean Six Sigma + PAT
ICH Q8: Pharmaceutical Development
ICH Q9: Quality Risk Management
ISO 9001
History of Quality
Goes back to B.C. 2150 Article 229 of famous Hammurabi laws states the following about quality:

"If a house built by a construction foreman is not robust enough and causes death by collapsing, that foreman shall be beheaded"

Quality was strictly followed by the Phoenicians too.

"If the product quality was below or outside the determined standards, the hand of the manufacturer of defective goods would be cut off"

History of Quality
Quality Assurance
It is the overall planned and systematic activities performed in order for the product to meet the defined requirements and sufficient assurance

Quality Concept in the
20th Century
1950s Sampling plans
1960s Zero - Defect
1980s ISO-9000
1990s QS-9000 & 6 Sigma
2000s Risk assessment approach

The Current Situation in the Pharmaceutical Industry
The process modifications required to be made on the improper formulations,

Instead of ensuring in-process product quality, performing post-process testing
Pharmaceutical Development Guideline
Based on manufacturing process understanding
Applicable to all drug products.
All development information
is not “mandatory”
The applicant can share prior knowledge for a more flexible regulatory approach.
Quality Risk Management
ICH Q9 serves as a guidance document;
To ensure a comon understanding of Quality Risk Management between industry and competent authorities

Pharmaceutical Quality System
Management Responsibility
Continual Improvement of Process Performance and Product Quality
Continual Improvement of the Pharmaceutical Quality System
Development and Manufacture of Drug Substances
Parallel to Q8
Covers chemical and biotechnological/biological entities
Developing and manufacturing API in the QbD framework
Based on Q8, Q9 and Q10
What Changes?
QbD – Quality by Design
Target Product Profile(TPP)
Quality Target Product Profile(QTPP)
Critical Quality Attributes(CQA)
Critical Process Parameters(CPP)
Statistical Tools
Design of Experiments(DoE)
Design Space(DS)
Target Product Profile (TPP)
Target Product Profile(TPP) guidance (FDA, 2007)
Dosage and Administration
Dosage forms/strengths
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in specific populations
Drug abuse and dependence
Clinical Pharmacology
Nonclinical Toxicology
Clinical studies
Storage and handling
Patient Counseling Information
Quality Target Product Profile (QTPP)
QTPP is a summary of the product’s quality attributes and characteristics
QTPP is a sub-branch of Target Product Profile (TPP)
Critical Quality Attributes (CQA)
A Critical Quality Attribute(CQA) is a physical, chemical, biological or microbiological attribute/characteristic that should be within an appropriate limit, range or distribution to ensure the desired product quality (ICH Q8).
Critical Process Parameters (CPP)
Critical Process Parameter (CPP) is ;
a process parameter whose variability has an impact on a critical quality attribute,
therefore should be monitored or controlled to ensure the process produces the desired quality (ICH Q8)
Design of Experiments (DoE)
The development of a design space, the important point in activity is proving or determining that uncategorized parameters left outside
What is PAT?
One of the tool for application of QbD is;
PAT – Key Points
Tools Used in QbD Studies
Data analysis
Data analysis with multiple variables are used for the correlation of the quality attributes of final dosage forms and process/formulation variables
Guidelines and mathematical models for easy establishment and independent use of knowledge
Artificial neural networks
Genetic algorithm
Fuzzy logic softwares
Multilayer perception neural networks
Neurofuzzy Logic

QbD Study in Ramipril Tablets
To evaluate the QbD principles, Ramipril was used as a model drug and produced tablets were designed with the application of INForm
Methods used in creation of the tablets;
Direct Compression
Wet Granulation
Spray Granulation
The CQAs (tablet hardness, dissolution in 30 minutes, assay, impurity C and impurity D) were determined upon risk control
Formulation and Process Parameters
Formulation and process parameters used in the methods of direct compression, wet granulation and spray granulation include the following:
Formulations prepared with the wet granulation method
A total of 128 formulas was studied in two laboratory series in these studies with specified formulation and process parameters
Finalization was initiated by performing the model formation and optimization studies with

FormRules (Neurofuzzy system)
Inform ANN (Artificial Neural Network)
Inform GEP (Genetic Algorithm)

programs by using these formulation and process parameters.
Wet Granulation-MgSt
Wet Granulation Study Result
According to visual histogram and optimization data for optimum formulation:
HPMC 0,443% - 0,644%
MgSt 1,046% - 1,076%
Drying temp. 51,2°C – 60°C/ needs to be performed using a vacuum system,
Moisture % 0,704 – % 0,950
Sieve size needs to be 0,125 mm. In concentrations falling between this values, trial studies have been performed on the laboratory series and completed product analysis have been performed.
It has been seen that the results generated are consistent with the optimization data. After the finished product analysis results, it has been planned to be taken to stability studies.
Wet Granulation-HPMC/SSF
Wet Granulation Study Result
According to visual histogram and optimization data for optimum formulation
HPMC 0,359% – 0,625%
SSF 1,2% –1,053%
Drying temp. 50°C – 60°C / needs to be performed using a vacuum system,
Moisture 0,50% –0,779%
Sieve size needs to be 0,125 mm. In concentrations falling between this values, trial studies have been performed on the laboratory series and completed product analysis have been performed.
It has been seen that the results generated are consistent with the optimization data. After the finished product analysis results, it has been planned to be taken to stability studies.
Examples of Wet GranulationResults
Wet granulation formulation and process parameters study result
Consequently it was observed that our study on the limits of formulation and process parameters specified in the study conducted with the wet granulation method had produced positive results
It is considered after the consideration of the Design Space that a
drying temperature of 45°C to 55°C
and not to reduce the
sieve size less than 1.25 mm
in order to ensure that impurity D would remain at a low value
QbD Study in Ramipril Tablets
This study showed that a huge amount of detailed data for QbD studies could be gained from ANN programs, that could not obtained with the routine R&D experiments

QbD – Quality by Design
QbD: A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management
(ICH Q8)
QTPP and CQA for Quality
The choice of ;
Type of delivery systems ,
API properties ,
Manufacturing properties,
Manufacturing platform ...
will influence the quality attributes that are critical to safety, efficacy and manufacturability
It belongs to me (Design Space)
Design Space
This is my science, this is my process provided by my science and this is how they are linked each other.
Vision of PAT
From …
Laboratory based, finished product testing
To …
On-Line, in-process testing

New developing techniques
Near-Infra Red (NIR) Spectroscopy
Raman Spectroscopy
X-Ray Microtomography
Nuclear Magnetic Resonance (NMR) Spectroscopy
TeraHertz Pulse Spectroscopy
Laser Induced Breakdown Spectroscopy
Acoustic Emission(AE)
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